The invention relates to medical applications of the HDAC inhibitor resminostat ((E)-3-[1-{4- dimethylaminomethyl-benzenesulfonyl)-1 H-pyrrol-3-yl]-N-hydroxy-acrylamide) or a salt or solvate thereof in the treatment of benign or malignant neoplasia in a human subject, wherein said human subject is an Asian, and said treatment comprises administering resminostat or a salt or solvate thereof to said human subject in a daily dose of less than 600 mg, and administering at least one further ehemotherapeutic agent to said human subject.

Known technical background

Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl groups from specific histone sites in particular at promotor and enhancer regions, which is an essential part of regulation of cellular gene transcription. HDACs also regulate gene expression in an indirect fashion by mediating the acetylation of non-histone proteins such as DNA-binding proteins, transcription factors, signal transducers, DNA repair and chaperon proteins (Ververis K et al., Biologies: Targets and Therapy 7: 47-60, 2013; Vitt D et al. , Targeting histone acetylation. In: RSC Drug Discovery Series No. 48: Epigenetics for Drug Discovery. Editor: Nessa Carey. The Royal Society of Chemistry, 2016).

Resminostat ((E)-3-[1-{4-dimethylaminomethyl-benzenesulfonyl)-1 H-pyrrol-3-yl]-N-hydroxy- acrylamide) is an orally available HDAC inhibitor histone-deacetylase (HDAC) inhibitor.

The Phase Ha SHELTER study (for further information on clinical trials, a search is available on https://clinicaltrials.gov) evaluated resminostat both as monotherapy and in combination with sorafenib as a second-line treatment of advanced HCC after proven radiological disease progression under first-line sorafenib therapy. The study met its primary endpoint both in the monotherapy arm and in the combination therapy. Patients receiving the resminosfat/sorafenib combination therapy showed a progression-free survival rate (PFSR) after 12 weeks of 70.0% and a median PFS of 5.4 months, resulting in a median overall survival (OS) of 8.1 months.

In the Phase II SAPHIRE trial in patients with advanced Hodgkin Lymphoma (HL), resminostat in monotherapy has demonstrated substantial anti-tumor activity, with an overall response rate of 34% and a clinical benefit in 54% of the patients in a heavily pre-treated patient population together with very good safety and tolerability. Furthermore, resminostat was studied in a Phase 1 dose escalation approach in advanced colorectal cancer (CRC) patients, evaluating resminostat in combination with the standard chemotherapeutic FOLFIRI regimen.

Recently, two Phase i/ll trials investigating resminostat in the indications of liver cancer (HCC) and non-smaii-ceil lung cancer (NSCLC) were finalized. These studies tested resminostat in Asian patients in combination treatment with conventional cancer drugs sorafenib (in HCC) and docetaxel (in NSCLC), in comparison to monotherapy with the respective cancer drug. Also, Phase 1 clinical trials are being conducted in biliary tract cancer and pancreatic cancer in Asian patients.

Sorafenib (4-[4-[[4-chloro-3-(thfluoromethyl)phenyl]carbamoylarnino]ph enoxy]-/V-rnethyl- pyridine-2-carboxamide; brand name Nexavar®), https://en.wikipedia.org/wiki/Sorafenib is an orally available protein kinase inhibitor from the group of multi-kinase inhibitors. It has been evaluated in a number of clinical studies and so far been approved for the treatment of advanced renal cell carcinoma, advanced hepatocellular carcinoma, and radioactive iodine resistant advanced thyroid carcinoma. HDAC inhibitors have been described to cause growth arrest with subsequent differentiation or apoptosis of tumor cells, whereas normal cells are not affected. As summarized in a review article by Marks et al. (Nature Reviews Cancer, 2001 , Volume 1 , page 194-202), HDAC inhibitors cause cell-cycle arrest in G1 and/or G2 phase. Growth-inhibitory effects have been documented in vitro in virtually ali transformed ceil types, including cell lines that arise from both hematological and epithelial tumors. The growth inhibitory cellular mechanism of the HDAC inhibitors has been described as a specific induction of expression of the cell cycle inhibitor CDKN1A (p21 ). Additionally, this review article summarizes the induction of growth arrest in tumor-bearing mice by HDAC inhibitors. Efficacy of HDAC inhibitors has been demonstrated in animal models of diverse cancer types such as breast, prostate, lung and stomach cancers, neuroblastoma and leukemias.

Treatment of many cancer types by HDAC inhibitors has been described in the available literature. HDAC inhibition has an effect on the expression of a number of proteins playing pivotal roles in tumor-relevant processes, such as HER2/neu, VEGF, raf-1 , cyclin A and B, Bax, Bad, p53, c-myc, Caspase 3, p21 and ERo. According to a review by Villar-Garea et ai.

(Int. J. Cancer: 1 12, 171-178 (2004)) cancer is understood to be an epigenetic as well as a genetic disease and the main goal using HDAC inhibitors would be restoration of gene expression of those tumor-suppressor genes that have been transcriptionally silenced by promotor-associated histone deacetylation. Drummond et al. (Annu. Rev, Pharmacol. Toxicol. 2005. 45:495-528) review the molecular mechanism and outcome of histone and non-histone substrates in cancer cells, which are effectors of HDAC, while HDAC also facilitates the acetylation of several key proteins other than histones. According to said review, acetylation is a key posttra relational modification of many proteins responsible for regulating critical intracellular pathways, and many of these substrates are tissue/development specific (EKLF, GATA-1 , ERct, MyoD), oncogenic (c-Myb), tumor-suppressing (p53), or even rather ubiquitous (TFIIE, TFIIF, TCF, HNF-4) transcription factors. Modulation of those proteins can lead to induction of cell cycle arrest, differentiation and apoptosis, all of which are desirable mechanisms for treatment of cancer. Kelly et al. (Expert Opin Invest Drugs, 1 1 (12), 2002) provides a further review on HDAC inhibitors in general and their application in cancer therapy.

The official US NIH website http://clinicaltrials.gov lists (status: February 2016) 545 clinical trials for cancer indications treated with HDAC inhibitors, among others various forms of Leukemia (e.g. CIVIL, CLL, AML), myelodysplasia syndrome, lymphoma including non- hodgkin's lymphoma, multiple myeloma, plasma cell neoplasm, solid tumors in general, small intestine cancer, mesothelioma, prostate, breast (male and female), lung cancer (including non-small and small cell), neuroendocrine, malignant epithelial neoplasms, pancreas, skin cancer (including melanoma), multiple myeloma, cervix, renal cell, head and neck, gastric, ovarian, liver cancer, colon, rectal, thymoma, fallopian tube, peritoneal, nasopharyngeal, vestibular schwannoma, meningioma, acoustic neuroma, neurofibromatosis type 2, thyroid, urothelial, gliomas, brain, esophagus, astrocytoma, anaplastic oligodendroglioma, giant cell glioblastoma, glioblastoma, gliosarcoma, mixed glioma, brain neoplasm, and ovarian.

WO 2005/087724 A2 describes certain N-sulphonylpyrrole derivatives, which are described to be used in the pharmaceutical industry for the production of pharmaceutical compositions.

WO 2007/39404 A1 describes novel N-sulphonylpyrrole derivatives and certain salts of these N-suiphonylpyrrole derivatives, which are described to be used in the pharmaceutical industry for the production of pharmaceutical compositions.

WO 2009/1 12529 A1 describes a specific production method of N-sulphonylpyrrole derivatives and salts thereof, which are described to be used in the pharmaceutical industry for the production of pharmaceutical compositions. Brief descri tion of the figures

Figure 1 shows a Comparison of AUC0-6h of the 800mg cohort of the Western and Asian Phase I studies, or Phase I part of these studies (cf. examples section).

Description of the invention

It has now been found that unexpectedly Asian patients under resminostat treatment couid benefit from different doses than those which, have previously been administered e.g. to Western / Caucasian patients.

The invention thus relates to medical applications of the HDAC inhibitor resminostat ((E)-3-[1- (4-Dimethyiaminomethyl-benzenesulfonyl)-1 H-pyrrol-3-yl]-N-hydroxy-acrylamlde) or a salt or solvate thereof in the treatment of benign or malignant neoplasia in a human subject, wherein said human subject is an Asian, and said treatment comprises administering resminostat or a salt or solvate thereof to said human subject in a daily dose of less than 600 mg, and administering at least one further chemotherapeutic agent to said human subject.

Certain embodiments of the present invention are listed in the following items:

1 . Use of resminostat or a salt or solvate thereof for the manufacture of a medicament for use in the treatment of benign or malignant neoplasia in a human subject, wherein said human subject is an Asian, and wherein said treatment comprises administering resminostat or a salt or solvate thereof to said human subject in a daily dose of less than 600 mg resminostat, and administering at least one further chemotherapeutic agent to said human subject.

2. Use of resminostat or a salt or solvate thereof for the treatment of benign or malignant neoplasia in a human subject, wherein said human subject is an Asian, and wherein said treatment comprises administering resminostat or a salt or solvate thereof to said human subject in a daily dose of less than 600 mg resminostat, and administering at least one further chemotherapeutic agent to said human subject.

3. Resminostat or a salt or solvate thereof for use in the treatment of benign or malignant neoplasia in a human subject, wherein said human subject is an Asian, and wherein said treatment comprises administering resminostat or a salt or solvate thereof to said human subject in a daily dose of less than 600 mg resminostat, and administering at least one further chemotherapeutic agent to said human subject. A method of treating benign or malignant neoplasia in a human subject in need thereof, wherein said human subject is an Asian, and wherein said method comprises administering resminostat or a salt or solvate thereof to said human subject in a daily dose of less than 600 mg resminostat, and administering a therapeutically effective amount of at least one further chemotherapeutic agent to said human subject. The use, Resminostat or a salt or solvate thereof for the use, or the method according to any of claims 1 to 5, wherein said further chemotherapeutic agent is a molecular targeted agent. The use, Resminostat or a salt or solvate thereof for the use, or the method according to any of items 1 to 5, wherein said further chemotherapeutic agent is a VEGFR inhibitor. Resminostat or a salt or solvate thereof for the use, the use or method according to any of items i to 6, wherein said further chemotherapeutic agent is sorafenib. Resminostat or a salt or solvate thereof for the use, the use or method according to any of items 1 to 7, wherein sorafenib is administered to said human subject in a daily dose of about 800 mg. Resminostat or a salt or solvate thereof for the use, the use or method according to claim 8, wherein said treatment comprises administering resminostat or a salt or solvate thereof and sorafenib with following biweekly dosing regimen: a : administering a daily dose of about 400mg resminostat for 5 days, followed by a period of 9 days drug withdrawal, and b : administering a daily dose of about 800mg of sorafenib. Resminostat or a salt or solvate thereof for the use, the use or method according to claim 9, which is characterized by reduction of the toxicity of Resminostat and/or Sorafenib and maintenance of antitumor activity. Resminostat or a salt or solvate thereof for the use, the use or method according to any of items 1 to 10, wherein said human subject is a member of the Southeast Asian or Northeast Asian genetic group. Resminostat or a salt or solvate thereof for the use, the use or method according to any of items 1 to 10, wherein said human subject is a member of the Samoyed, Mongol, Tibetan, Korean, Japanese, Ainu, South Chinese, Mon Khmer, Thai, Indonesian, Philippine, or Malaysian genetic group.

13. Resminostat or a salt or solvate thereof for the use, the use or method according to any of items 1 to 10, wherein said human subject is a member of the Northeast Asian genetic group.

14. Resminostat or a salt or solvate thereof for the use, the use or method according to any of items 1 to 10, wherein said human subject is a member of the Samoyed, Mongol, Tibetan, Korean, Japanese, or Ainu genetic group.

15. Resminostat or a salt or solvate thereof for the use, the use or method according to any of items 1 to 10, wherein said human subject is a member of the Korean or Japanese genetic group.

18. Resminostat or a salt or solvate thereof for the use, the use or method according to any of items 1 to 15, wherein said salt of resminostat is resminostat mesylate salt.

17. Resminostat or a salt or solvate thereof for the use, the use or method according to any of items 1 to 16, wherein said benign or malignant neoplasia is cancer, particularly hepatocellular cancer.

In the present invention, the daily dose of resminostat is less than 600 mg, particularly 550 mg or less, more particularly 500 mg or less, even more particularly 500 mg or less, even more particularly 450 mg or less, even more particularly 400 mg or less, even more particularly 350 mg or less, even more particularly 300 mg or less, even more particularly 250 mg or less, even more particularly 200 mg or less.

As used herein, resminostat (which is an International Non-proprietary Name, i.e. INN) and (E)-3-[1-(4-Dimethylaminomethyl-benzenesulfonyl)-1 H-pyrrol-3-yl]-N-hydroxy-acrylamide (its chemical name) are used interchangeably and both refer to a compound of the following formula:

o

/ o In particular embodiments of the present invention, said further chemotherapeutic agent is a kinase inhibitor, particularly a class 3 kinase inhibitor, a RAF inhibitor, a VEGFR inhibitor, particularly a VEGFR inhibitor from the group of multikinase inhibitors or tyrosine kinase inhibitors, even more particularly a VEGFR inhibitor selected from the group consisting of Sunitinib, Sorafenib, Ramucirumab und Vatalanib, yet even more particularly Sorafenib.

As used herein, a molecular targeted agent is a chemotherapeutic agent that acts through specific interactions with one or more molecular targets, e.g. proteins in the patient. This is opposed to agents that act through non-specific interactions, such e.g. genera! cytotoxic agents that act through DNA intercalation or DNA modifications such as alkylation or DNA crosslinking.

As used herein, sorafenib (which is an International Non-proprietar Name) and 4-[4-[[4- ch!oro-3-(trif!uoromethyl)phenyl]carbamoylamino]phenoxy]-/V- methyl-pyridine-2-carboxamide

(its chemical name) are used interchangeably and both refer to a compound of the below formula. Sorafenib is also known under its trade name Nexavar®.

Suitable salts for resminostat are acid addition salts or salts with bases. Particular mention may be made of the pharmacologically tolerable inorganic and organic acids and bases customarily used in pharmacy. Those suitable are, on the one hand, water-insoluble and, particularly, water-soluble acid addition salts, the acids being employed in salt preparation in an equimolar quantitative ratio or one differing therefrom, particularly in an equimolar quantitative ratio. On the other hand, salts with bases are - depending on substitution - also suitable, the bases being employed in salt preparation in an equimolar quantitative ratio or one differing therefrom. Pharmacologically intolerable salts, which can be obtained, for example, as process products during the preparation of resminostat on an industrial scale, are converted into pharmacologically tolerable salts by processes known to the person skilled in the art. According to the invention, resminostat as well as its salts may contain, e.g. when isolated in crystalline form, varying amounts of solvents. Included within the scope of the invention are therefore all solvates and in particular all hydrates of resminostat as well as all solvates and in particular all hydrates of resminostat, in particular such solvates or hydrates comprising about 0,5, 1 or 2 solvate or water molecules per molecule of resminostat or salts thereof.

Particular salts in the context of the present invention are the salts of resminostat with methanesulfonic acid, in particular in a molar ratio of about 1 :1.

Resminostat and salts thereof can be prepared, for example, as described in detail in WO 2005/087724 A2, WO 2007/39404 A1 and WO 2009/1 12529 A1 , respectively. Sorafenib is commercially available and methods of its preparation are well-known.

The genetic groups "Asian" "Southeast Asian, Northeast Asian, Samoyed, Mongol, Tibetan, Korean, Japanese, Ainu, South Chinese, Mon Khmer, Thai, Indonesian, Philippine, or Malaysian" mentioned herein are to be understood as classified in Cavalli-Sforza, enozzi and Piazza, "The History and Geography of Human Genes", 1994, Princeton University Press (ISBN: 9780691087504).

The term "Asian" is herein particularly defined to be a person having aboriginal origins or having ancestors, e.g. at least one parent with aboriginal origins in the Far East or Southeast Asia, including in particular for example, China, Mongolia, Taiwan, Singapore, Korea, Japan, Vietnam, Cambodia, Laos, Burma, Thailand, Malaysia, Indonesia and Philippines, but more particularly excluding the Indian subcontinent.

In the present invention, subjects can also be specified as Asians, or any of the specific groups included of the definition of Asians as defined herein, by self-identification {e.g. by a questionnaire) or by assignment by a physician on the basis of their somatic traits and/or their country of origin or the country of origin of their ancestors.

Asian descent can also be determined by microsatellite markers as described in the known literature.

The biological and medicinal properties of resminostat and its respective salts, as well as of sorafenib are described in detail in the prior art, including the references cited herein. Cancer, as used herein, and also known as malignant neoplasia, is a medical condition characterized by tumor cells metastasizing into distinct organs or tissues. Examples of malignant neoplasia treated with the embodiments of the present invention include solid and hematological tumors. Solid tumors are exemplified by tumors of the breast, bladder, bone, brain, central and peripheral nervous system, colon, endocrine glands (e.g. thyroid and adrenal cortex), esophagus, endometrium, germ cells, head and neck, kidney, liver, lung, larynx and hypopharynx, mesothelioma, ovary, pancreas, prostate, rectum, renal, small intestine, soft tissue, testis, stomach, skin, ureter, vagina and vulva. Malignant neoplasia includes inherited cancers exemplified by Retinoblastoma and Wilms tumor. In addition, malignant neoplasia includes primary tumors in said organs and corresponding secondary tumors in distant organs ("tumor metastases"). Hematological tumors are exemplified by aggressive and indolent forms of leukemia and lymphoma, namely non-Hodgklns disease, chronic and acute myeloid leukemia (CML / AML), acute lymphoblastic leukemia (ALL), Hodgkin's disease, multiple myeloma and T-cell lymphoma. Also included are myelodysplastic syndrome, plasma cell neoplasia, paraneoplastic syndromes, cancers of unknown primary site, as well as AIDS related malignancies.

Particular cancer types in the context of the present invention are hepatocellular cancer (HCC), non-small cell lung cancer (NSCLC), pancreatic cancer, biliary tract cancer and cutaneous T-cell lymphoma (CTCL), more particularly HCC, CTCL and NSCLC,

In general, malignant tumors differ from benign tumors in four biological properties: structure, rate of growth, invasive growth, and disseminated growth by metastasis. Common for both benign and malignant tumors is the abnormal proliferation of ceils. Since HDAC inhibitors can inhibit proliferation by regulation of cell cycle dependent genes and proteins or induce cell cycle arrest, which has been demonstrated for malignant tumors, it is apparent that HDAC inhibitors can also be used for the treatment of benign neoplasia.

Particular forms of benign neoplasia in the context of the present invention are colonic polyps, adenoma, papilloma, cystadenoma, liver cell adenoma, hydatiform moles, renal tubular adenoma, squamous cell papilloma, gastric polyps, hemangioma, osteoma, chondroma, lipoma, fibroma, lymphangioma, leiomyoma, rhabdomyoma, astrocytoma, nevi, meningioma, ganglioneuroma, and endometriosis. For information on endometriosis and HDAC, see Reprod Sci. 2012 ay; 19(5):483-92.

Drug resistance is of particular importance for the frequent failure of standard cancer therapeutics. This drug resistance is caused by various cellular and molecular mechanisms like overexpression of drug efflux pumps, mutation within the cellular target protein or fusion proteins formed by chromosomal translocations. The commercial applicability of resminostat is not limited to 1 ^st line treatment of patients. Patients with resistance to cancer chemotherapeutics or target specific anti-cancer drugs can be also amenable for treatment with resminostat for e.g. 2 ^nd or 3 ^rd line treatment cycles. A prominent example is given by acute promyelocytic leukemia patients with the PML-RARa fusion protein, resistant to standard therapy with retinoids. These patients can be resensitized towards retinoids by treatment with HDAC inhibitory drugs like resminostat. in the present invention, resminostat and the at least one further chemotherapeutic agent may be administered, simultaneously, sequentially or separately.

In the further context of the present invention the term "active agents" refers to a compound exerting a medical effect on a disease or medical condition (e.g. an amelioration thereof) and said term in particular includes resminostat and sorafenib.

In the embodiments of the invention, the active agents may be provided in pharmaceutical compositions comprising one or more of said active agents and a pharmaceutically acceptable carrier or diluent. In particular, resminostat and sorafenib may be provided in the same pharmaceutical composition (also known as a fixed combination) or in separate pharmaceutical compositions (e.g. in two separate tablets).

Such pharmaceutical compositions may be provided in the context of pharmaceutical products, comprising e.g. one or more pharmaceutical compositions and packaging material. Said packaging material typically comprises a label or package insert which indicates that the active agent(s) is/are useful for treating the diseases detailed herein. The packaging material, label and package insert otherwise parallel or resemble what is generally regarded as standard packaging material, labels and package inserts for pharmaceuticals having related utilities.

The pharmaceutical compositions according to this invention are prepared by processes which are known per se and familiar to the person skilled in the art. As pharmaceutical compositions, the active agents are either employed as such, or preferably in combination with suitable pharmaceutical auxiliaries and/or excipients, e.g. in the form of tablets, coated tablets, capsules, caplets, suppositories, patches (e.g. as TTS), emulsions, suspensions, gels or solutions, the active agent content advantageously being between 0.1 and 95% and where, by the appropriate choice of the auxiliaries and/or excipients, a pharmaceutical administration form (e.g. a delayed release form or an enteric form) exactly suited to the active agent and/or to the desired onset of action can be achieved.

The person skilled in the art is familiar with auxiliaries, vehicles, excipients, diluents, carriers or adjuvants which are suitable for the desired pharmaceutical formulations, preparations or compositions on account of his/her expert knowledge. In addition to solvents, gel formers, ointment bases and other excipients, for example antioxidants, dispersants, emulsifiers, preservatives, soiubiiizers, colorants, complexing agents or permeation promoters, can be used.

Depending upon the particular type of benign or malignant neoplasia to be treated, additional therapeutically active agents, which are normally administered to treat said benign or malignant neoplasia, may optionally be co-administered with resminostat and sorafenib.

Examples of such additional therapeutically active agents are known chemotherapeutic anticancer agents used in cancer therapy, including, but not are limited to (i) alkylating/carbamylating agents such as Cyclophosphamid (Endoxan®), Ifosfamid (Holoxan®), Thiotepa (ThiotehpaLederle®), elphalan (Alkeran®), or chloroethylnitrosourea

(BCNU); (ii) platinum derivatives like cis-platin (Platinex® BMS), oxaliplatin or carboplatin (Cabroplat® BMS); (iii) antimitotic agents / tubulin inhibitors such as vinca alkaloids (vincristine, vinblastine, vinorelbine), taxanes such as Taxol (Paclitaxel®), Taxotere (Docetaxel®) and analogs as well as new formulations and conjugates thereof; (iv) topoisomerase inhibitors such as anthracyclines (exemplified by Doxorubicin / Adriblastin®), epipodophyllotoxines (examplified by Etoposide / Etopophos®) and camptothecin analogs (exemplified by Topotecan / Hycamtin®); (v) pyrimidine antagonists such as 5-fluorouracil (5- FU), Capecitabine (Xeloda®), Arabinosyicytosine / Cytarabin (Alexan®) or Gemcitabine (Gemzar®); (vi) purin antagonists such as 6-mercaptopurine (Puri-Nethol®), 6-thioguanine or fludarabine (Fludara®) and finally (vii) folic acid antagonists such as methotrexate (Farmitrexat®).

Examples of target specific anti-cancer drug classes used in experimental or standard cancer therapy include but are not limited to (i) kinase inhibitors such as e.g. Glivec (Imatinib®), ZD- 1839 / Iressa (Gefitinib®), SU 1 1248 (Sutent®) or OSI-774 / Tarceva (Erlotinib®); (ii) proteasome inhibitors such as PS-341 (Velcade®); (iii) heat shock protein 90 inhibitors like 17-allylaminogeldanamycin (17-AAG): (iv) vascular targeting agents (VTAs) and anti- angiogenic drugs like the VEGF antibody Avastin (Bevacizumab®) or the KDR tyrosine kinase inhibitor PTK787 / ZK222584 (Vatalanib®); (v) monoclonal antibodies such as Herceptin (Trastuzumab®) or MabThera / Rituxan (Rituximab®), mutants as well as conjugates of monoclonal antibodies and antibody fragments; (vi) oligonucleotide based therapeutics like G-3139 / Genasense (Oblimersen®); (vii) protease inhibitors (viii) hormonal therapeutics such as anti-estrogens (e.g. Tamoxifen), anti-androgens (e.g. Flutamide or Casodex), LHRH analogs (e.g. Leuprolide, Goserelin or Triptorelin) and aromatase inhibitors. Other known anti-cancer agents which can be used for combination therapy include bleomycin, retinoids such as all-trans retinoic acid (ATRA), DNA methyltransferase inhibitors such as the 2-deoxycytidine derivative Decitabine (Docagen®), alanosine, cytokines such as interleukin-2, interferons such as interferon «2 or interferon--,-, TRAIL, DR4/5 agonistic antibodies, FasL and TNF-R agonists and finally histone deacetylase inhibitors different to sulphonylpyrrole derivatives as described in the present invention such as SAHA, PXD101 , MS275, GCD0103, Depsipeptide / FK228, NVP-LBH589, valproic acid (VPA) and butyrates.

As exemplary anti-cancer agents for use in combination with the compounds according to this invention in the co-therapies mentioned herein the following drugs may be mentioned, without being restricted thereto, 5 FU, actinomycin D, abarelix, abciximab, aclarubicin, adapalene, alemtuzumab, altretamine, aminoglutethimide, amiprilose, amrubicin, anastrozole, ancitabine, artemisinin, azaihioprine, basiliximab, bendamustine, bicalutamide, bleomycin, broxuridine, busulfan, capecitabine, carboplatin, carboquone, carmustine, cetrorelix, chlorambucil, chlormethine, cisplatin, cladribine, clomifene, cyclophosphamide, dacarbazine, daclizumab, dactinomycin, daunorubicin, deslorelin, dexrazoxane, docetaxel, doxifluridine, doxorubicin, droloxifene, drostanolone, edelfosine, eflornithine, emitefur, epirubicin, epitiostanol, eptaplatin, erbitux, estramustine, etoposide, exemestane, fadrozole, finasteride, floxuridine, flucytosine, fludarabine, fluorouracil, flutamide, formestane, foscarnet, fosfestrol, fotemustine, fulvestrant, gefitinib, gemcitabine, g!ivec, goserelin, gusperimus, herceptin, idarubicin, idoxuridine, ifosfamide, imatinib, improsulfan, infliximab, irinotecan, ianreotide, !etrozole, leuprorelin, lobaplatin, lomustine, melphalan, mercaptopurine, methotrexate, meturedepa, miboplatin, mifepristone, miltefosine, mirimostim, mitoguazone, mitolactol, mitomycin, mitoxantrone, mizoribine, motexafin, nartograstim, nebazumab, nedaplatin, nilutamide, nimustine, octreotide, ormeloxifene, oxaliplatin, paclitaxel, palivizumab, pegaspargase, pegfilgrastim, pentetreotide, pentostatin, perfosfamide, piposulfan, pirarubicin, plicamycin, prednimustine, procarbazine, propagermanium, prospidium chloride, raltitrexed, ranimustine, ranpimase, rasburicase, razoxane, rituximab, rifampicin, ntrosulfan, romurtide, ruboxistaurin, sargramostim, satraplatin, sirolimus, sobuzoxane, spiromustine, streptozocin, tamoxifen, tasonermin, tegafur, temoporfin, temozolomide, teniposide, testolactone, thiotepa, thymalfasin, tiamiprine, topotecan, toremifene, trastuzumab, treosu!fan, triaziquone, trimetrexate, triptorelin, trofosfamide, uredepa, valrubicin, verteporfin, vinblastine, vincristine, vindesine, vinorelbme and vorozole.

Other known anti-cancer agents which can be used for combination therapy include agents commonly known as immune checkpoint inhibitors or short checkpoint inhibitors, i.e. agents that inhibit inhibitory checkpoint molecules, such as the inhibitory checkpoint molecules Adenosine A2A receptor (A2AR), B7-H3 (also called CD276), B7-H4 (also called VTCN1 ), B and T Lymphocyte Attenuator (BTLA, also called CD272), short for Cytotoxic T-Lymphocyte- Associated protein 4 (CTLA-4, also called CD152), Indoleamine 2,3-dioxygenase (IDO), Killer-cell Immunoglobulin-iike Receptor (KIR), Lymphocyte Activation Gene-3 (LAGS), Programmed Death 1 receptor (PD-1 ), as well as Programmed Death 1 receptor Ligand (PD- L1 ), T-cell Immunoglobulin domain and Mucin domain 3 (TIM-3), V-domain Ig suppressor of T cell activation (VISTA, also called C10orf54). Examples of such checkpoint inhibitors include MGA271 (by acroGenics), Ipilimumab (Yervoy*), Tremelimumab (formerly CP-675,206), Lirilumab, B S-986016 (by BMS), BMS-936559/MDX-1 105 (by BMS), Pembroiizumab (Keytruda ^® ), Nivolumab (Opdivo ^® ), Ga!iximab, IMP321 (by Immuntep), BMS-663513 (by BMS), PF-05082566 (by Pfizer), IPH2101 (by Innate Pharma / BMS), KW-0761 (by Kyowa Kirin), CDX-1 127 (by CellDex Therapeutics), MEDI-6469 (by Medlmmune/ AstraZeneca), MEDI4736 (by AstraZeneca),CP-870,893 (by Genentech), Pidiiizumab, MPDL3280A (by Genentech), AMP-514 (by Medlmmune/AZ), MEDI4736 (by Medlmmune/AZ), AUNP 12 peptide (by Aurigene and Pierre Fabre), SB0010718C (by Merck Serono)

In practicing the present invention and depending on the details, characteristics or purposes of their uses mentioned above, the active agents according to the present invention may be administered in combination therapy separately, sequentially, simultaneously or chronologically staggered (e.g. as combined unit dosage forms, as separate unit dosage forms or adjacent discrete unit dosage forms, as fixed or non-fixed combinations, as kit-of- parts or as admixtures).

A "fixed combination" is defined as a combination wherein a first active ingredient (e.g. resminostat) and at least one further active ingredient (e.g. sorafenib) are present together in one unit dosage or in a single entity. One example of a "fixed combination" is a pharmaceutical composition wherein the said first active ingredient and said further active ingredient are present in admixture for simultaneous administration, such as in a single formulation. Another example of a "fixed combination" is a pharmaceutical combination wherein the said first active ingredient and the said further active ingredient are present in one unit without being in admixture.

A "kit-of-parts" is defined as a combination wherein the said first active ingredient and the said further active ingredient are present in more than one unit. One example of a "kit-of-parts" is a combination wherein the said first active ingredient and the said further active ingredient are present separately. The components of the kit-of-parts may be administered separately, sequentially, simultaneously or chronologically staggered. The first and further active ingredient of a combination or kit-of-parts according to this invention may be provided as separate formulations {i.e. independently of one another), which are subsequently brought together for simultaneous, sequential, separate or chronologically staggered use in combination therapy; or packaged and presented together as separate components of a combination pack for simultaneous, sequential, separate or chronologically staggered use in combination therapy.

The type of pharmaceutical formulation of the first and further active ingredient of a combination or kit-of-parts according to this invention can be similar, i.e. both ingredients are formulated in separate tablets or capsules, or can be different, i.e. suited for different administration forms, such as e.g. one active ingredient is formulated as tablet or capsule and the other is formulated for e.g. intravenous administration.

A further aspect of the present invention is a combination comprising, in non-fixed form, resminostat or a salt thereof, in particular resminostat mesylate (i.e. methanesuifonate), and one or more art-known standard therapeutic, in particular art-known chemotherapeutic or target specific anti-cancer agents, such as those mentioned above, in particular sorafenib, for sequential, separate, simultaneous or chronologically staggered use in therapy in any order. Optionally said combination comprises instructions for its use in therapy.

A further aspect of the present invention is a combined preparation, such as e.g. a kit of parts, comprising a preparation of resminostat or a salt thereof and a pharmaceutically acceptable carrier or diluent; a preparation of a further active ingredient, in particular sorafenib, and a pharmaceutically acceptable carrier or diluent; and optionally instructions for simultaneous, sequential, separate or chronologically staggered use in therapy.

A further aspect of the present invention is a kit of parts comprising a dosage unit of resminostat or a salt thereof, a dosage unit of a further active ingredient, in particular sorafenib, and optionally instructions for simultaneous, sequential or separate use in therapy.

A further aspect of the present invention is a pharmaceutical product comprising resminostat, or one or more pharmaceutical compositions comprising said compounds; and one or more art-known therapeutic agents, in particular sorafenib, or one or more pharmaceutical compositions comprising said therapeutic agents, for simultaneous, sequential or separate use in therapy. Optionally this pharmaceutical product comprises instructions for use in said therapy. A further aspect of the present invention is a pharmaceutical composition as unitary dosage form comprising, in admixture, resminostat or a salt thereof, a further active ingredient, which is an art-known standard therapeutic, in particular sorafenib, and optionally a pharmacologically acceptable carrier, diluent or excipient.

A further aspect of the present invention is a commercial package comprising resminostat or a salt thereof together with instructions for simultaneous, sequential or separate use with one or more art-known standard therapeutic, in particular sorafenib. In addition, the combination according to the present invention can be used in the pre- or post-surgical treatment of benign or malignant neoplasia.

In further addition, the combination according to the present invention can be used in combination with radiation therapy, in particular in sensitization of patients towards standard radiation therapy.

The administration of the combination according to the present invention and pharmaceutical compositions according to the invention may be performed in any of the generally accepted modes of administration available in the art. Illustrative examples of suitable modes of administration include intravenous, oral, nasal, parenteral, topical, transdermal and rectal delivery. Oral and intravenous delivery are preferred.

In the embodiments of the present invention, doses refer to the amount of compound with respect to the free form of said compound, i.e. the free acid or free base form of said compound. Consequently, adducts, salts, etc. of such free acid or free base form are actually to be administered in a correspondingly higher dose in order to account for the weight of the counter-ion or adduct partner. For example, in relation to resminostat mesylate salt, a "dose of 400 mg resminostat" relates to (rounded) 510 mg resminostat mesylate salt - comprising 400 mg resminostat free base and 1 10 mg methanesulfonic acid (molecular weight of resminostat = 349,4; molecular weight of resminostat mesylate salt = 445,5; therefore 400 : 349,4 ^* 445,5 = 510).

Having described the invention in detail, the scope of the present invention is not limited only to those described characteristics or embodiments. As will be apparent to persons skilled in the art, modifications, analogies, variations, derivations, homologisations and adaptations to the described invention can be made on the base of art-known knowledge and/or, particularly, on the base of the disclosure (e.g. the explicit, implicit or inherent disclosure) of the present invention without departing from the spirit and scope of this invention as defined by the scope of the appended claims.

In the present invention, the administration of active agents may follow a certain schedule, which may include periods of daily administration of active agents and periods wherein no active agents are administered. For example, such a schedule may consist of repeating cycles of 5 days of active agents (or resminostat) administration followed by 9 days wherein no active agents are administered ("rest period") (14-day cycle), 5 days of active agents (or resminostat) administration followed by 18 days of rest period (21 -day cycle), or 14 days of active agents (or resminostat) administration followed by 7 days of rest period (21 -day cycle).

Examples

The following examples serve to illustrate the invention further without restricting it.

Clinical studies;

First-in-Man study (FIM; 7341/EM-001 ): This was an open-label, dose-escalation, phase I study of orally administered resminostat in patients with advanced malignancies. The study was conducted in the UK. Patients with histologically or cytoiogically documented primary or metastatic solid tumors refractory to standard therapy or for which no standard therapy existed were included. Tumors were to be progressive (new or progressive lesions or rising PSA). In addition, patients were to have good performance status (ECOG 0-1 ), adequate hepatic, renal, cardiac and bone marrow function and an estimated life expectancy of greater than 12 weeks. Treatment with resminostat consisted of once daily oral administration on Days 1 to 5 followed by 9 days of rest during 14-day treatment cycles. Sequential cohorts of patients were treated with escalating doses of resminostat, including 7 patients at 800 mg.

SAPHIRE (4SC-201 -2-2009): This was an open-label, phase II study of orally administered resminostat in patients with advanced Hodgkin's lymphoma (HL). The primary objective of the study was to determine the objective response rate (ORR) of repeated oral doses of resminostat. Secondary objectives were to evaluate safety and tolerability, efficacy, pharmacokinetics and pharmacodynamics of treatment with resminostat. Endpoints included OS, PFS, TTP and duration of response (DOR). The study was conducted at 5 centers in the Czech Republic, Poland and Romania. Patients with histologically or cytoiogically proven, relapsed or refractory HL, based on the International Working Group (IWG) response criteria, were included in this study. Patients should have good performance status (ECOG 0-1 ) and adequate hepatic, renal, cardiac and bone marrow function. During the main part of the study, patients were treated with 600 mg or 800 mg resminostat once daily on Days 1 to 5 followed by 9 days of rest during 14-day treatment cycles. Patients were treated for at least 12 weeks (8 treatment cycles) or until tumor progression. After 12 weeks, patients without progressive disease had the option to continue treatment with resminostat for up to one year in the follow- up part of the study.

SHORE (4SC-201-3-2010): This was an open-label phase l/l I study of orally administered resminostat in patients with advanced colorectal carcinoma (CRC). Resminostat was administered in combination with the standard FOLFIRI regimen. The phase I dose escalation part of the study was conducted at 2 centers in Germany. Patients with histologically or cytologically confirmed advanced stage CRC were included in this study. Patients should have received previous treatment for advanced CRC and been foreseen for chemotherapy with FOLFIRI in second or third line therapy. The main eligibility criteria included a performance status of ECOG 0-2, adequate hepatic, renal, cardiac and bone marrow function and a life expectancy ≥ 12 weeks. Treatment consisted of once or twice daily oral administration of resminostat on Days 1 to 5 followed by 9 days of rest during 14-day treatment cycles. FOLFIRI was administered on Days 3 and 4 of each resminostat treatment cycle. During dose-escalation, sequential cohorts of 3-8 patients were treated with escalating doses, of which 8 patients received 2x 400 mg resminostat + FOLFIRI daily.

Study YHI-1001 -ST-01 : This was an open-label phase I study of orally administered resminostat in Asian patients with advanced solid tumors. The primary objectives of the study were to determine the maximum tolerated dose (MTD) of resminostat in the Asian patient population based on dose-limiting toxicities (DLTs) and safety. Secondary objectives were to evaluate pharmacokinetics, pharmacodynamics and efficacy of repeated oral doses of resminostat. The study was conducted at a single center in Japan. Patients with histologically or cytologically confirmed advanced solid tumors who have failed standard therapies or for whom no treatment options were available were included in this study. The main eligibility criteria included a performance status of ECOG 0-1 , adequate hepatic, renal, cardiac and bone marrow function and a life expectancy of more than 12 weeks. Sequential cohorts of 3-6 patients were treated with escalating doses of 400 mg (N=3), 600 mg (N=3) or 800 mg (N=6) resminostat once daily on Days 1 to 5 followed by 9 days of rest during 14 day treatment cycles. In total, 12 patients were treated for at least 2 treatment cycles or until tumor progression or patient withdrawal. Study YHI-1001-HCC-02: This is an open-label, multi-center Phase l/l I study in patients with advanced HCC previously untreated with systemic chemotherapy (first-line therapy) to determine the MTD and to evaluate safety and efficacy of resminostat in combination with sorafenib in the Asian patient population. The study is conducted in Japan and Korea. The main eligibility criteria included a performance status of ECOG 0-1 , adequate hepatic, renal, cardiac and bone marrow function and a life expectancy of more than 12 weeks.

In the Phase I part, sequential cohorts of 3-6 patients were treated with escalating doses of 400 mg (N=3) or 600 mg (N=6) resminostat in combination with 800 mg sorafenib. Treatment consisted of administration of a daily dose of 400mg resminostat for 5 days, followed by a period of 9 days drug withdrawal during 14-day treatment cycles and .administration of a daily dose of SOOmg Sorafenib. In total, 9 patients were treated for at least 2 treatment cycles or until tumor progression or patient withdrawal. At dose of 400 mg resminostat, 2 patients achieved partial response (PR) and 1 patient had stable disease (SD). At dose of 600 mg resminostat, none of patients achieved PR and 4 patients had SD. Only one dose limiting toxicity, which is grade 4 thrombocytopenia, was observed at dose of 600 mg resminostat The main toxicity which was observed during the first 2 cycles and related to resminostat administration is shown in the below table 3. Collection and preparation of piasma samples:

Venous blood samples (2 ml) were collected in 3 ml K ₂ EDTA vacutainers (Becton Dickinson 13x75 mm), then carefully swiveled 8-10 times and put on ice. Within 15 minutes after blood collection, samples were centrifuged for 10 min at 2700 x g and +4°C. The supernatant (plasma) was transferred into a polypropylene tube and immediately frozen at -80°C,

PK measurement:

For each PK measurement, 200 pL of human plasma sample were added to 50 pL of internal standard working solution (20 pg/L D ₆ - esminostat [di(tri-deutero-methyl)-aminomethyl- derivative] in human plasma) in a 96-well deep-well block. Subsequently, 600 μί. of diisopropyl ether/isoamyl alcohol (80/20 v/v) were pipetted into each cavity. After sealing the deep-well block, vigorous automated mixing {5 min) was followed by centrifugation (5 min, 3000 rpm). 500 pL of the (upper) organic layer from each well was transferred to a second deep-weil plate. After evaporation under a stream of nitrogen the residue was reconstituted with 30 pL of DMSO and 30 pL of water. 10 pL were injected into a 2 pL-sample loop for HPLC-MS/MS analysis. Chromatography was performed on a Luna (Phenomenex®) C18, 5 pm, 100 A, 50 mm x 2 mm analytical column at a flow-rate of 0.5 mL/min in the dual column mode employing a column switching technique. Mobile phase A: 5 mM ammonium formate (315.3 mg/L) in water containing 0.2% formic acid, v/v; Mobile phase B: 5 mM ammonium formate (315.3 mg/L) in acetonitrile/water 95/5 (v/v) containing 0.2% formic acid, v/v;

Gradient: Time (minutes) % Solvent B

0.00 5

1.00 5

3.00 50 3.01 100

4.00 100

4.01 5

Mass spectrometry was performed on an API 3000 (MDS Sciex) triple quadrupole mass spectrometer in the MRM-mode (multiple reaction monitoring) with the TurbolonSpray® interface. The mass spectrometer was operated in the positive ion mode using a linear gradient from 4.75% to 95% acetonitrile in 5 mM aqueous ammonium formate. The selected precursor- and product-ions for Resminostat were at m/z 350.0 and m/z 317.0, respectively. The selected precursor- and product-ions for the interna! standard were at m/z 356.2 and m/z 323.0, respectively. The lower limit of quantification (LLOQ) for BYK409578 was 0.100 pg/L with an upper limit of quantification (ULOQ) of 100 pg/L based 200 μΙ_ of human plasma. The standard curves were linear using weighted linear regression analysis (1/x2; concentration- squared weighting). The coefficients of correlation (r) for the calibration curves ranged from 0.9965 to 0.9988.

Adverse Events

Both in the FIM dose finding study, and in the YHI-1001 -ST-01 dose finding study, adverse events related to resminostat administration were recorded. The results regarding cytopenias are shown in the below tables.

Table 1 : Study FIM; 7341/EM-001 - Western / Caucasian Patients

Table 2: Study YHI-1 001-ST-01 - Japanese Patients

400 mg 600 mg 800 mg

Dose

N=3 N=3 N=6

Ali Grade Ali Grade Ali Grade

Grade

grades 3/4 grades 3/4 grades 3/4

Lymphopenia 2 1 1

Lymphopenia 1 2 2 6 2

Neutropenia 1 2 1 2 1

Thrombocytopenia 2 2 5 3

Leucopenia 1 3 1 2 1 Tabie 3: Study YHI-1001-HCC-02 - Japanese Patients

400 mg 600 mg

Dose

N=3 N=6

All Grade All Grade

Grade

grades 3/4 grades 3/4

Thrombocytopenia 100% 83% 50%

Lymphopenia 33% 67% 17%

Leucopenia - 50%

From the results of the Phase ! part, dose of 400 mg resminostat in combination with sorafenib showed higher effectiveness and tolerability than dose of 600 mg resminostat.

Whereas only single incidences of cytopenias occurred in Western patients, more Asian patients had such events upon treatment with resminostat.

Particularly, doses of 600 mg/day show increases in cytopenias in Asian patients, which was not observed in Western patients, and while 400 mg/day are well tolerated in Asian patients.

PK comparison Western / Asian

Exploratory data analysis and determination of the AUG values was based on non- com pa rtmenta I analysis (NCA) performed on the studies listed below, using the software program WinNonLin. A comparison of the AUC _0- 6h of the respective 800mg cohorts from the Asian and Western Phase I patients (Combined FIM, SAPHIRE and SHORE vs. Study YHI- 1001-ST-01 ) at cycle , dayl results in no significant difference (two tailed t-test) between mean AUC Western vs. Asian. The results are shown in Figure 1.

These results show that the effect on tolerability in Asian patients is independent of pharmacokinetic effects.